PROJECT SUMMARY Efforts to create a cancer genomic commons are already underway, yet data sharing practices face daunting challenges. Ulti- mately, a genomic knowledge commons will only be successful if appropriate data-sharing policies that address disincentives for sharing and implementation challenges are developed and mapped onto the institutions and actors who can enact such change. In our previous work (McGuire R01HG006460), experts ranked data-sharing as the most important, yet least politically tractable policy challenge among 17 posed in a modified Delphi process. The objective of this proposal is to engage expert advisors and relevant stakeholders to identify and rank challenges, generate policy solutions, and translate findings into action in a specific domain poised to make progress, to ensure the success of a cancer genomic commons. Throughout the project, we will engage our expert multi-disciplinary advisory com- mittee to solicit their input. In Aim 1, we will conduct a historical case study of the knowledge commons that exists in cancer genomics, as well as identify alternative frameworks for data sharing practices. In Aim 2, we will analyze the case study and conduct qualitative interviews with stakeholders in relevant constituencies to identify and further examine the challenges identi- fied in Aim 1. In Aim 3, we will employ a policy Delphi process with advisory committee members to refine, rank, and generate solutions to key policy issues. In Aim 4, we will take the policy map from Aims 1-3 and tailor findings and policy options to specific target audiences, and present information in a form they can use. This contribution is significant because it addresses a pressing clinical need to interpret the clinical significance of genomic variants, and to build infrastructure and practices to advance scientific understanding of cancer genomics. It will provide information needed to structure a cancer genomic com- mons. A sustainable, effective commons is critical to the integration of genomic information in the management of inherited cancer risk, as well as advancing understanding of cancer biology. The approach is innovative by engaging a diverse and repre- sentative group of stakeholders, providing them with several sources of systematic empirical input to identify policy challenges, generate solutions and map those to the appropriate institutions and actors. It is also innovative in translating findings and options through systematic policy engagement. The work is feasible in our hands because our team of established investigators have expertise in ethical and policy issues related to large-scale data sharing and a track record of success working together on large collaborative projects addressing ethical and policy issues in genomics. Sulston Project: cancer genomic variant commons 22-line summary 1